Robustness of arterial blood gas analysis for assessment of respiratory safety pharmacology in rats

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• 作者：Garth T. Whiteside^a ; ^{Garth.Whiteside@pharma.com" class="auth_mail" title="E-mail the corresponding author} ; Michele Hummel^a ; ^{Michelle.Hummel@pharma.com" class="auth_mail" title="E-mail the corresponding author} ; Jamie Boulet^b ; ^{JamieBoulet@productsafetylabs.com" class="auth_mail" title="E-mail the corresponding author} ; Jessica D. Beyenhof^b ; ^{JessicaBeyenhof@productsafetylabs.com" class="auth_mail" title="E-mail the corresponding author} ; Bryan Strenkowski^a ; ^b ; ^{BryanStrenkowski@productsafetylabs.com" class="auth_mail" title="E-mail the corresponding author} ; Janet Dell John^b ; ^{JanetDellJohn@productsafetylabs.com" class="auth_mail" title="E-mail the corresponding author} ; Terri Knappenberger^a ; ^{Terri.Knappenberger@pharma.com" class="auth_mail" title="E-mail the corresponding author} ; Harry Maselli^b ; ^{HarryMaselli@productsafetylabs.com" class="auth_mail" title="E-mail the corresponding author} ; Lee Koetzner^b ; ^{LeeKoetzner@productsafetylabs.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Morphine sulfate (PubChem CID ; 5464280) ; Buprenorphine (PubChem CID ; 644073) ; Oxycodone hydrochloride (PubChem CID ; 5462350) ; Hydrocodone bitartrate (PubChem CID ; 20831824) ; Fentanyl citrate (PubChem CID ; 13810)
• 刊名：Journal of Pharmacological and Toxicological Methods
• 出版年：2016
• 出版时间：March-April 2016
• 年：2016
• 卷：78
• 期：Complete
• 页码：32-41
• 全文大小：3002 K

文摘

Whole body plethysmography using unrestrained animals is a common technique for assessing the respiratory risk of new drugs in safety pharmacology studies in rats. However, wide variations in experimental technique make cross laboratory comparison of data difficult and raise concerns that non-appropriate conditions may mask the deleterious effects of test compounds — in particular with suspected respiratory depressants. Therefore, the objective of this study was to evaluate the robustness of arterial blood gas analysis as an alternative to plethysmography in rats. We sought to do this by assessing the effect of different vehicles and times post-surgical catheterization on blood gas measurements, in addition to determining sensitivity to multiple opioids. Furthermore, we determined intra-lab variability from multiple datasets utilizing morphine and generated within a single lab and lastly, inter-lab variability was measured by comparing datasets generated in two separate labs. Overall, our data show that arterial blood gas analysis is a measure that is both flexible in terms of experimental conditions and highly sensitive to respiratory depressants, two key limitations when using plethysmography. As such, our data strongly advocate the adoption of arterial blood gas analysis as an investigative approach to reliably examine the respiratory depressant effects of opioids.